Composition and method to alleviate joint pain using a mixture of fish oil and fish oil derived, choline based, phospholipid bound fatty acid mixture including polyunsaturated epa and dha

ABSTRACT

Beneficial and synergistic effects for alleviating joint pain and symptoms of osteoarthritis and/or rheumatoid arthritis have been found using a mixture of fish oil and fish oil derived, choline based, phospholipid bound fatty acid mixture including polyunsaturated EPA and DHA either alone or in combination with other active constituents, including astaxanthin and polymeric hyaluronic acid or sodium hyaluronate (hyaluronan) in an oral dosage form.

RELATED APPLICATION(S)

This is a continuation-in-part application of prior filed applicationSer. No. 12/840,372 filed Jul. 21, 2010, which is based on provisionalapplication Ser. No. 61/227,872, filed Jul. 23, 2009; and provisionalapplication Ser. No. 61/345,652, filed May 18, 2010, the disclosureswhich are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to treating and alleviating symptoms ofosteoarthritis and/or rheumatoid arthritis using therapeuticcompositions and methods derived from a mixture of fish oil and fish oilderived, choline based, phospholipid bound fatty acids includingpolyunsaturated EPA and DHA either alone or admixed with synergisticadditives.

BACKGROUND OF THE INVENTION

The '372 parent application identified above is directed to theadvantageous use of krill oil such as disclosed in U.S. PatentPublication Nos. 2004/0234587; 2004/0241249; and 2007/0098808, thedisclosures which are hereby incorporated by reference in theirentirety. The beneficial and therapeutic advantages of krill oil arediscussed in the various research endeavors that are mentioned in theBackground of the Invention section of the '372 application. Such anexample is a krill oil manufactured by Neptune Technologies in which adaily dose of about 300 mg reduces arthritic symptoms within a shorttreatment period of about 7 to 14 days as determined by standard WOMACscoring procedures.

The '372 application later describes the beneficial and synergisticeffects for alleviating joint pain and symptoms of osteoarthritis and/orrheumatoid arthritis when krill oil is used in combination with otheractive constituents. It has now been found advantageous to use otheroils containing certain phospholipid bound polyunsaturated fatty acidsnot derived from krill in combination with fish oil.

SUMMARY OF THE INVENTION

In accordance with a non-limiting example, even more beneficial andsynergistic effects for alleviating joint pain and symptoms ofosteoarthritis and/or rheumatoid arthritis have been found when of amixture of fish oil and fish oil derived, choline based, phospholipidbound fatty acids including polyunsaturated EPA and DHA is used incombination with other active constituents.

In accordance with a non-limiting example, the method treats andalleviates symptoms of osteoarthritis and/or rheumatoid arthritis in apatient by administering a therapeutic amount of a composition includinga mixture of fish oil and a fish oil derived, choline based,phospholipid bound fatty acids including polyunsaturated EPA and DHA incombination with astaxanthin and low molecular weight polymers ofhyaluronic acid or sodium hyaluronate (hyaluronan) in an oral dosageform.

The mixture of fish oil and fish oil derived, choline based,phospholipid bound fatty acids including polyunsaturated EPA and DHA inone example comprises Eicosapentaenoic (EPA) and Docosahexaenoic (DHA)fatty acids in the form of both triacylglycerides anddiacylphospholipids. In one example, the mixture of fish oil and fishoil derived, choline based, phospholipid bound fatty acids includingpolyunsaturated EPA and DHA comprises not less than 15 g/100 g of fishderived phospholipids, not less than 12 g/100 g of DHA, and not lessthan 7 g/100 g of EPA. In another example, the mixture of fish oil andfish oil derived, choline based, phospholipid bound fatty acidsincluding polyunsaturated EPA and DHA comprises not less than 22 g/100 gof omega-3 and no less than 3 g/100 g of omega-6. The mixture of fishoil and fish oil derived, choline based, phospholipid bound fatty acidsincluding polyunsaturated EPA and DHA can be further concentrated bysupercritical fluid solvent extraction of fish oil triacylglyceridesfrom the choline based phospholipids to decrease fish oiltriacylglycerides and increase fish oil derived phospholipids.

In another example, the mixture of fish oil and fish oil derived,choline based, phospholipid bound fatty acids including polyunsaturatedEPA and DHA includes at least 15% EPA and 9% DHA, of which not less than45% are in the form of phospholipids. The composition can be deliveredadvantageously for therapeutic results with 1-4000 mg of a mixture offish oil and fish oil derived, choline based, phospholipid bound fattyacids including polyunsaturated EPA and DHA delivered per daily dose. Inanother example, 0.1-50 mg astaxanthin are added to the mixture of fishoil and fish oil derived, choline based, phospholipid bound fatty acidsincluding polyunsaturated EPA and DHA per daily dose. In one example,the phospholipids comprise 30% or less of the composition.

The astaxanthin is preferably derived from Haematococcus pluvialisalgae, Pfaffia, krill, or by synthetic routes, in the free diol,monoester or diester form or any mixture thereof. The hyaluronic acid orsodium hyaluronate (hyaluronan) can be derived from microbialfermentation or animal tissues. About 1-500 mg of hyaluronan can bedelivered per daily dose. In a preferred example, the hyaluronic acid isderived from a biofermenation process and has a surprisingly lowmolecular weight between 0.5 and 100 kilodaltons (kDa). In anotherexample, the polymers of hyaluronic acid or sodium hyaluronate(hyaluronan) are derived from animal tissue and have molecular weightsfar exceeding 100 kDa. Such high molecular weight hyaluronans aretypically derived from rooster combs and are reportedly mildlyanti-inflammatory though this fact is somewhat controversial. Theliterature clearly indicates that as the molecular weight of hyaluronicacid and its salts increases, its immunogenicity drops dramatically. Inaddition, more recent scientific literature suggests that low molecularweight hyaluronic acids fragments are unexpectedly highlypro-inflammatory with respect to the innate immune system and would thusnot be expected to be useful in the treatment of inflammatory diseasestates and in particular joint pain associated with OA and/or RH.

The composition may also include a natural or synthetic cyclooxygenase-1or -2 inhibitor comprising aspirin, acetaminophen, steroids, prednisone,or NSAIDs. The composition may also include a gamma-linoleic acid richoil comprising Borage (Borago officinalis L.) or Safflower (Carthamustinctorius L.).

The composition may also include an n-3 (omega-3) fatty acid rich oilderived from fish oil (EPA and DHA), algae oil (EPA and DHA), flax seedoil (ALA), perilla seed oil(ALA) or chia seed oil(ALA) and the n-3 fattyacid comprises, either alone or in combination, alpha-linolenic,stearidonic, eicosapentaenoic or docosapentaenoic acid. Soluble orinsoluble forms of collagen and elastin such as those derived fromhydrolyzed or un-hydrolyzed eggshell membrane can also be advantageouslyadded. The composition may also include anti-inflammatory and/or jointhealth promoting compounds comprising at least one of the preparationsof the green lipped mussel (Perna canaliculus), Boswellia serrata,turmeric (Curcuma Longa), stinging nettle (Urtica dioica), Andrographis,Cat's claw (Uncaria tomentosa), bromelain, methylsulfonylmethane (MSM),chondroitin sulfate, glucosamine hydrochloride or glucosamine sulfate,s-adenosyl-methionine, proanthocyanidins, or flavonoids, andpreparations of hydrolyzed or un-hydrolyzed eggshell membrane. Thecomposition may include naturally-derived and/or synthetic antioxidantsthat are added to retard degradation of polyunsaturated fatty acids suchas a tocopherol, tocotrienol, carnosic acid or carnisol or mixturesthereof either with or without the potent anti-oxidant astaxanthin.

Different compositions may use different ingredients in combination withthe mixture of fish oil and fish oil derived, choline based,phospholipid bound fatty acids including polyunsaturated EPA and DHA ,astaxanthin and hyaluronate and be combined with different ingredientsand supplemental ingredients for more specific purposes.

A pharmaceutically acceptable composition comprises a mixture of fishoil and fish oil derived, choline based, phospholipid bound fatty acidsincluding polyunsaturated EPA and DHA in combination with astaxanthinand hyaluronate and optionally combined with glucosamine sulfate or itshydrochloride salt, chondroitin sulfate, hydrolyzed or unhydrolyzedcollagen, elastin methylsulfonmethane, a gamma-linoleic acid or omega-3fatty acid rich oil or a cyclooxgenase or lipoxygenase inhibitor for thetreatment of symptoms related to joint pain or joint diseases includingbut not limited to osteoarthritis and rheumatoid arthritis.

In yet another example, a dietary supplement acceptable compositioncomprises mixture of fish oil and a fish oil derived, choline based,phospholipid bound fatty acid mixture including polyunsaturated EPA andDHA in combination with astaxanthin and hyaluronate and optionallycombined with glucosamine sulfate or its hydrochloride salt, chondroitinsulfate, hydrolyzed or unhydrolyzed collagen, elastinmethylsulfonmethane, a gamma-linoleic acid or omega-3 fatty acid richoil and a cyclooxgenase and/or lipoxygenase inhibitor for the treatmentof symptoms related to joint pain or joint diseases including but notlimited to osteoarthritis and rheumatoid arthritis.

In yet another example, a medical food acceptable composition comprisesa mixture of fish oil and fish oil derived, choline based, phospholipidbound fatty acid mixture including polyunsaturated EPA and DHA incombination with astaxanthin and hyaluronate and optionally combinedwith glucosamine sulfate or its hydrochloride salt, chondroitin sulfate,hydrolyzed or unhydrolyzed collagen, elastin methylsulfonmethane, agamma-linoleic acid or omega-3 fatty acid rich oil and a cyclooxgenaseand/or lipoxygenase inhibitor for the treatment of symptoms related tojoint pain or joint diseases including but not limited to osteoarthritisand rheumatoid arthritis.

In still another example, a composition is formulated in a therapeuticamount to treat and alleviate symptoms of osteoarthritis and/orrheumatoid arthritis, wherein the composition includes a mixture of fishoil and fish oil derived, choline based, phospholipid bound fatty acidmixture including polyunsaturated EPA and DHA in combination withastaxanthin and polymers of hyaluronic acid or sodium hyaluronate(hyaluronan) in an oral dosage form. This composition may include otheractive constituents as explained and identified above relative to themethod and composition.

A method to treat and alleviate symptoms of osteoarthritis and/orrheumatoid arthritis in a patient is disclosed by administering acomposition comprising a therapeutic amount of omega choline. In anotherexample, the omega choline is administered with hyaluronic acid ofvarying molecular weights. In another example, therapeutic compositionincludes a mixture of fish oil and fish oil derived, choline based,phospholipid bound fatty acid mixture including polyunsaturated EPA andDHA admixed with hyaluronic acid of varying molecular weights andastaxanthin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will now be described more fully hereinafter. Thisinvention may, however, be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth herein. Rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey the scope of the invention to thoseskilled in the art.

The composition includes EPA and DHA functionalized as EPA and DHA boundcholine based phospholipids and acyltriglycerides derived from a mixtureof fish oil and fish oil derived, choline based, phospholipid boundfatty acid mixture including polyunsaturated EPA and DHA astaxanthin,and in one non-limiting example, low molecular weight polymers ofhyaluronic acid or sodium hyaluronate (hyaluronan) in an oral dosageform. In other examples, the hyaluronic acid has varying molecularweights.

As noted before, surprisingly the composition includes apro-inflammatory low molecular weight Hyaluronic Acid (LMWtHA). Naturalhigh molecular weight hyaluronic acid is the major hydrodynamiccomponent of synovial fluid and importantly is known to beimmuno-neutral to the innate immune system. It is nature's bone jointshock absorbent and lubricant. It has been found that there is excellentoral bioavailability of LMWtHA fragments specifically to connectivetissue, which maximizes interaction with targeted cell receptors whichmay mediate the innate immune response in diseased joints. Therefore ina preferred composition containing a mixture of fish oil and fish oilderived, choline based, phospholipid bound fatty acid mixture includingpolyunsaturated EPA and DHA and astaxanthin two anti-inflammatorycomponents and LMWtHA are thus combined with one highly inflammatorycomponent. The scientific literature indicates that LMWtHA fragments inin vitro studies has been shown to exhibit potent pro-inflammatorybehavior. It therefore remains unclear why a pro-inflammatory componentwould elicit a favorable overall response in inflamed joint tissues. Itis believed that such pro-inflammatory LMWtHA fragments may promote siterepair by simulation of the innate immune system repair mechanism and bysimulating production of non-immunogenic high molecular weight HAbringing the joint back to homeostasis, however these are merelyunproven theories. A great deal of work by leading immunologists isstill attempting to unravel all the aspects of the complicated singlingprocesses associated with the innate immune system. Studies using largeanimal models of osteoarthritis have shown that mild immunogenicHyaluronic Acids with molecular weights within the range of 0.5-1.0×10⁶Da (Dalton) were generally more effective in reducing indices ofsynovial inflammation and restoring the rheological properties of SF(visco-induction) than non-immunogenic HA's with molecular weights>2.3×10⁶ Da. This treatment evolved from treating horses with sterileinjections of such hyuronates.

Astaxanthin is a component of the instant invention in some examples.Related scientific literature indicates that in a lipopolysaccharideinduced inflammatory rat model, astaxanthin at just 1 mg/kg in vitro andin vivo: (1) down regulates TNF-alpha production by 75%; (2) downregulates prostaglandin E-2 production (PGE-2) by 75%; (3) inhibitsnitric oxide synthase (NOS) expression of nitric oxide by 58%; and (4)these effects on inflammatory markers were nearly as effective asprednisolone in this model. Such information suggests but does not provethat astaxanthin may be an effective standalone product for thereduction of OA and/or RH pain or other symptomology associated with OAand/or RH however high doses of astaxanthin are required to achieve suchanti-inflammatory results to date.

In induced uveitis, astaxanthin also showed dose dependant ocularanti-inflammatory activity by suppression of NO, PGE-2 and TNF-Alpha bydirectly blocking NO synthase activity. Astaxanthin is also known toreduce C-Reactive Protein (C-RP) blood levels in vivo. For example, inhuman subjects with high risk levels of C-RP three months of astaxanthintreatment resulted in 43% of patients serum C-RP levels to drop belowthe risk level. This may explain why C-RP levels dropped significantlyin the referenced Deutsch study. Astaxanthin is so powerful that it hasbeen shown to negate the pro-oxidant activity of Vioxx in in vitroexperiments, a COX-2 inhibitor belonging to the NSAIDS drug class whichis now known to cause cellular membrane lipid per-oxidation leading toheart attack and stroke and was thus removed from the US pharmaceuticalmarket. Astaxanthin is absorbed in vitro by lens epithelial cells whereit suppresses UVB induced lipid per-oxidative mediated cell damage atumol/L concentrations. In human trials astaxanthin at 4 mgs/dayprevented post exercise joint fatigue following strenuous knee exercisewhen compared to untreated subjects. These results have been shown in:

-   1) Lee et al., Molecules and Cells, 16(1):97-105; 2003;-   2) Ohgami et al., Investigative Ophthalmology and Visual Science    44(6):2694-2701, 2003;-   3) Spiller et al., J. of the Amer. College of Nutrition, 21(5):    October 2002; and-   4) Fry et al., Univ. of Memphis Human Performance Laboratories, 2001    and 2004, Reports 1 & 2.

A preferred composition in one embodiment includes 300 mg of krill oil,45 mg of low molecular weight HA, and 2 mg astaxanthin.

Astaxanthin has potent singlet oxygen quenching activity. Astaxanthintypically does not exhibit pro-oxidant activity unlike β-carotene,lutein, zeaxanthin and Vitamins A and E. Astaxanthin in some studies hasbeen found to be about 50 times more powerful than Vitamin E, 11 timesmore powerful than β-carotene and three times more powerful than luteinin quenching of singlet oxygen. Astaxanthin is also well known for itsability to quench free radicals. Comparative studies have foundastaxanthin to be 65 times more powerful than Vitamin C, 54 times morepowerful than β-carotene, 47 times more powerful than lutein, and 14times more powerful than Vitamin E in free radical quenching ability.

Studies have shown that HA binds to the surface of dendritic cells(“DC's”) and stimulated T-cells. Blockade of the CD44-HA interactionleads to impaired T-Cell activation both in vitro and in vivo. Studieshave also shown that in cancer cell lines, LMWtHA fragments specificallyinduce nitric oxide synthase, a pro-inflammatory cytokine, in dendriticcells. In DC's, NO expression caused dendritic cell apoptosis (celldeath). DC's are essential T-cell activators which function bypresenting antigens to T-cells, thus apoptosis of DC's may short circuitthe adaptive immune system response. This effect was clearly CD44dependent because pretreatment of DC's with anti-CD44 monoclonalantibodies blocked the NO mediated induction of DC apoptosis. It appearsthat low molecular weight HA fragments interrupt the normal course ofthe well known T-cell mediated adaptive immune system response. CD44 isa glycoprotein responsible in part for lymphocyte activation (also knownas T-cell activation) and is known to specifically bind to HA. On theother hand, as previously discussed, low molecular weight HA fragmentsappear to up-regulate the innate immune response, particularly inchronic inflammatory conditions where the innate immune system may insome way be compromised.

Support for such teachings can be found in:

-   1) Mummert et al., J. of Immunol. 169, 4322-4331;-   2) Termeer et al., Trends in Immunology, Vol. 24, March 2003;-   3) Yang et al., Cancer Res. 62, 2583-2591; and-   4) KcKee et al., J. Biol. Chem. 272, 8013-8018.

Additional information can be found in the following references: GhoshP. Guidolin D. Semin Arthritis Rheum., 2002 August; 32(1):10-37; and P.Rooney, M. Wang, P. Kumar and S. Kumar, Journal of Cell Science 105,213-218 (1993).

The '372 parent application discusses the beneficial aspects of usingkrill oil in synergistic combination with other ingredients. It has beendetermined that a fish oil and fish oil derived, choline based,phospholipid bound fatty acid mixture including polyunsaturated EPA andDHA is also advantageous for the treatment of some joint disease stateseither alone or admixed with other ingredients. One commerciallyavailable example of a mixture of fish oil and fish oil derived, cholinebased, phospholipid bound fatty acid mixture including polyunsaturatedEPA and DHA is Omega Choline 1520F as a phospholipid, omega-3preparation, which is derived from natural fish oil and sold byEnzymotec Ltd. One example of such composition is described below:

Ingredients (g/100 g): Pure Marine Phospholipids n.l.t. 15 DHA* n.l.t.12 EPA** n.l.t. 7 Omega-3 n.l.t. 22 Omega-6 <3 Analytical Data: Peroxidevalue (meq/Kg) n.m.t. 5 Loss on Drying (g/100 g) n.m.t. 2 PhysicalProperties: Consistency Viscous Liquid *Docosahexaenoic acid**Eicosapenteanoic acid

Astaxanthin has an excellent safety record. A study conducted by Stewartet al. 2008 obtained the following results:

Oral LD 50: 600 mg/kg (rats);

NOAEL: 465 mg/kg (rats); or

Serum Pharmacokinetics:

1) T_(1/2): 16 hours;

2) T_(max): 8 hours;

3) C_(max): 65 μg/L.

At eight weeks of supplementation at 6 mg per day, there was no negativeeffect in healthy adults. Spiller et al. 2003.

In accordance with one non-limiting example, astaxanthin has two primaryrenewable sources, namely a 1% to 12% astaxanthin oleoresin extractedfrom the micro algae Haematococcus pluvialis or 1.5-2.5% beadlet derivedfrom the same microalgae.

In accordance with a non-limiting example, the method treats andalleviates symptoms of osteoarthritis and/or rheumatoid arthritis in apatient by administering a therapeutic amount of a composition includinga mixture of fish oil and fish oil derived, choline based, phospholipidbound fatty acid mixture including polyunsaturated EPA and DHA incombination with astaxanthin and pro-inflammatory low molecular weightpolymers of hyaluronic acid or sodium hyaluronate (hyaluronan) in anoral dosage form. The mixture of fish oil and fish oil derived, cholinebased, phospholipid bound fatty acid mixture including polyunsaturatedEPA and DHA in one example comprises Eicosapentaenoic (EPA) andDocosahexaenoic (DHA) fatty acids in the form of triacylglycerides andphospholipids, although not less than 1% EPA and 5% DHA has been foundadvantageous. In another example, the omega choline includes at least15% EPA and 9% DHA, of which not less than 45% are in the form ofphospholipids. The composition can be delivered advantageously fortherapeutic results with 1-4000 mg of a mixture of fish oil and fish oilderived, choline based, phospholipid bound fatty acid mixture includingpolyunsaturated EPA and DHA delivered per daily dose. In anotherexample, 0.1-20 mg astaxanthin are supplemented to the omega choline perdaily dose.

It should be understood that an instant formulation can be used for therelief of joint discomfort that includes only a mixture of fish oil andfish oil derived, choline based, phospholipid bound fatty acid mixtureincluding polyunsaturated EPA and DHA. It is possible to use a mixtureof fish oil and fish oil derived, choline based, phospholipid boundfatty acid mixture including polyunsaturated EPA and DHA mixed withhyaluronic acid of varying molecular weights or a mixture of fish oiland fish oil derived, choline based, phospholipid bound fatty acidmixture including polyunsaturated EPA and DHA mixed with hyaluronic acidof varying molecular weights and astaxanthin. It should also beunderstood that an enriched version of a mixture of fish oil and fishoil derived, choline based, phospholipid bound fatty acid mixtureincluding polyunsaturated EPA and DHA can be used wherein the fractionof added fish oil diluents has been decreased and the proportion of fishoil derived phospholipids has been increased. This can be accomplishedby using supercritical CO2 and/or solvent extractions for selectiveremoval of triacylglycerides from phospholipids. In one example, themixture of fish oil and fish oil derived, choline based, phospholipidbound fatty acid mixture including polyunsaturated EPA and DHA comprisesnot less than 15 g/100 g of marine phospholipids, not less than 12 g/100g of DHA, and not less than 7 g/100 g of EPA. In another example, themixture of fish oil and fish oil derived, choline based, phospholipidbound fatty acid mixture including polyunsaturated EPA and DHA comprisesnot less than 22 g/100 g of omega-3 and less than 3 g/100 g of omega-6.

It should also be understood that although the hyaluronic acid has beendescribed as having low molecular weight, the mixture of fish oil andfish oil derived, choline based, phospholipid bound fatty acid mixtureincluding polyunsaturated EPA and DHA can be mixed with hyaluronic acidof varying molecular weights depending on circumstances of use.

The astaxanthin is preferably derived from Haematococcus pluvialisalgae, Pfaffia, krill, or by synthetic routes, in the free diol,monoester or diester form at a daily dose of 0.5-8 mg. The polymers ofhyaluronic acid or sodium hyaluronate (hyaluronan) can be derived frommicrobial fermentation or animal tissues. About 1-500 mg of hyaluronancan be delivered per daily dose and preferably between 10 and 70mgs/dose. In another example, the hyaluronic acid is derived from abio-fermenation process and has a molecular weight between 0.5 and 100kilodaltons (kDa). In another example, the polymers of hyaluronic acidor sodium hyaluronate (hyaluronan) are derived from microbialfermentation or animal tissue and have molecular weights exceeding 100KDa and preferably up to 10⁶ KDa.

The composition may also include a natural or synthetic cyclooxygenase-1or -2 inhibitor comprising for example aspirin, acetaminophen, steroids,prednisone, or NSAIDs. The composition may also include a gamma-linoleicacid rich oil comprising Borage (Borago officinalis L.) or Safflower(Carthamus tinctorius L.), which delivers a metabolic precursor to PGE₁synthesis.

The composition may also include an n-3 (omega-3) fatty acid rich oilderived from fish oil, algae oil, flax seed oil, chia seed oil orperilla seed oil and the n-3 fatty acid comprises alpha-linolenic,stearidonic, eicosapentaenoic or docosapentaenoic acid. Hydrolyzed orunhydrolyzed collagen and elastin derived from eggshell membranes canalso be advantageously added. The composition may also includeanti-inflammatory and/or natural joint health promoting compoundscomprising at least one of preparations of green lipped mussel (Pernacanaliculus), Boswellia serrata, turmeric (Curcuma Longa), stingingnettle (Urtica dioica), Andrographis, Cat's claw (Uncaria tomentosa),bromelain, methylsulfonylmethane (MSM), chondroitin sulfate, glucosaminesulfate or its hydrochloride salt, s-adenosyl-methionine,proanthocyanidins, or flavonoids. The composition may includenaturally-derived and synthetic antioxidants that are added to retarddegradation of fatty acids such as tocopherols, tocotrienols, carnosicacid or Carnosol and/or astaxanthin.

Different compositions may use different ingredients in combination withthe a mixture of fish oil and fish oil derived, choline based,phospholipid bound fatty acid mixture including polyunsaturated EPA andDHA, astaxanthin and hyaluronate and be combined with differentingredients and supplemental compositions for more specific purposes.

A pharmaceutically acceptable composition comprises a mixture of fishoil and fish oil derived, choline based, phospholipid bound fatty acidmixture including polyunsaturated EPA and DHA in combination withastaxanthin and hyaluronate optionally combined with one or moreingredients including but not limited to glucosamine sulfate,chondroitin sulfate, collagen, methylsulfonmethane, a gamma-linoleicacid or omega-3 fatty acid rich oil, a cyclooxgenase inhibitor or alipoxygenase inhibitor for the treatment of symptoms related to jointdiseases including but not limited to osteoarthritis and rheumatoidarthritis.

In yet another example, a dietary supplement acceptable compositioncomprises a mixture of fish oil and fish oil derived, choline based,phospholipid bound fatty acid mixture including polyunsaturated EPA andDHA in combination with astaxanthin and hyaluronate optionally combinedone or more ingredients, including but not limited to, glucosaminesulfate, chondroitin sufate, collagen, methylsulfonmethane, agamma-linoleic acid or omega-3 fatty acid rich oil a cyclooxgenaseinhibitor or a lipoxygenase inhibitor for the treatment of symptomsrelated to joint diseases including but not limited to osteoarthritisand rheumatoid arthritis.

In yet another example, a medical food acceptable composition comprisesa mixture of fish oil and fish oil derived, choline based, phospholipidbound fatty acid mixture including polyunsaturated EPA and DHA incombination with astaxanthin and hyaluronate and optionally combinedwith one or more ingredients including glucosamine sulfate, chondroitinsufate, collagen, methylsulfonmethane, a gamma-linoleic acid or omega-3fatty acid rich oil, a cyclooxgenase inhibitor or a lipoxygenaseinhibitor for the treatment of symptoms related to joint diseasesincluding but not limited to osteoarthritis and rheumatoid arthritis.

In still another example, a composition is formulated in a therapeuticamount to treat and alleviate symptoms of osteoarthritis and/orrheumatoid arthritis, wherein the composition includes a mixture of fishoil and fish oil derived, choline based, phospholipid bound fatty acidmixture including polyunsaturated EPA and DHA in combination withastaxanthin and polymers of hyaluronic acid or sodium hyaluronate(hyaluronan) in an oral dosage form. This composition may include otheractive constituents as explained and identified above relative to themethod and composition.

Osteoarthritis (OA) is the most prevalent form of arthritis.Osteoarthritis is a disease in which the cartilage that acts as acushion between the bones in joints begins to wear away causing bone onbone joint swelling and joint pain. It is characterized by degenerationof articular cartilage along with a peri-articular bone response. Itaffects both sexes, mainly in the fourth and fifth decades of life. Theknee joint is most commonly affected joint. At present the management isby pharmacological and non-pharmacological therapy. Corrective surgicaltherapy and or joint replacement therapy in some cases may not bepossible.

Traditional treatments for Osteoarthritis involve the use of analgesics,non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2specific (COX-2) NSAIDs alone or in combination with other activeanalgesics including but not limited to opiods or steroids. Advances inrecombinant protein synthesis also provide relief from the symptoms ofOA and RH by the use of genetically engineered proteins with specificfunctionality. Steroids or high molecular weight hyaluronic acidinjections have also been used with some success, however, thesetherapies have well known deleterious side effects.

Many of these treatments alone have shown limited effectiveness inclinical trials. To avoid the cardiac risks and gastrointestinal issuesassociated with traditional OA treatments (particularly with long termuse), many patients have turned to complimentary and alternativemedicines (CAMs) such as dietary supplements. Glucosamine andchondroitin alone or in combination, are widely marketed as dietarysupplements to treat joint pain due to OA. A major clinical trial onglucosamine and chondroitin (The GAIT Study) failed to show anysignificant improvement in WOMAC scores over placebo except in thehighest quartile of patients studied. Because of their limitedeffectiveness, the search for additional CAMs to treat OA continues (seefor example Ruff et al., Eggshell membrane in the treatment of pain andstiffness from Osteoarthritis of the knee: a randomized, multicenter,double-blind, placebo-controlled clinical study, Clin. Rheumatol (2009)28:907-914).

Many modifications and other embodiments of the invention will come tothe mind of one skilled in the art having the benefit of the teachingspresented in the foregoing descriptions and the associated drawings.Therefore, it is understood that the invention is not to be limited tothe specific embodiments disclosed, and that modifications andembodiments are intended to be included within the scope of the appendedclaims.

1-64. (canceled)
 65. A method to treat and alleviate symptoms of jointpain in a patient by administering a therapeutic amount of a dietarysupplement composition including a marine based oil comprisingphospholipids and at least one of polyunsaturated EPA and DHA incombination with astaxanthin and low molecular weight hyaluronic acid orsodium hyaluronate (hyaluronan) having a molecular weight of less than230 kilodaltons (kDa) in an oral dosage form.
 66. The method accordingto claim 65, wherein the low molecular weight hyaluronic acid or sodiumhyaluronate (hyaluronan) has a molecular weight of between 0.5 and 100kilodaltons (kDa).
 67. The method according to claim 65, wherein themarine based oil comprises Eicosapentaenoic (EPA) and Docosahexaenoic(DHA) fatty acids in the form of triacylglycerides and phospholipids.68. The method according to claim 65, wherein the marine based oilcomprises not less than (n.l.t.) 15 g/100 g of phospholipids, n.l.t. 12g/100 g of DHA, and n.l.t. 7 g/100 g EPA.
 69. The method according toclaim 65, and further comprising enriching the phospholipid fraction ofthe marine based oil from supercritical solvent extraction oftriacylglycerides from phospholipids.
 70. The method according to claim65, and further comprising delivering 0.1-20 mg astaxanthin supplementedto the marine based oil per daily dose.
 71. The method according toclaim 65, wherein the astaxanthin is derived from Haematococcuspluvialis algae, Pfaffia, krill, or by synthetic routes, in the freediol, monoester or diester form.
 72. The method according to claim 65,wherein the hyaluronic acid or sodium hyaluronate (hyaluronan) isderived from microbial fermentation or animal tissue.
 73. The methodaccording to claim 72, wherein the hyaluronic acid is derived from abiofermenation process.
 74. The method according to claim 65, whereinthe composition includes a natural or synthetic cyclooxygenase-1 or -2inhibitor comprising at least one of aspirin, acetaminophen, steroids,prednisone, and NSAIDs and/or a natural or synthetic lipoxygenaseinhibitor, including Boswellia serrata.
 75. The method according toclaim 65, wherein the composition includes a gamma-linoleic acid richoil comprising Borage (Borago officinalis L.) or Safflower (Carthamustinctorius L.).
 76. The method according to claim 65, wherein thecomposition includes an n-3 (omega-3) fatty acid rich oil comprising atleast one of fish oil, algae oil, flax seed oil, perilla seed oil andchia seed oil, and the n-3 fatty acid comprises at least one ofalpha-linolenic, stearidonic, eicosapentaenoic or docosapentaenoic acid.77. The method according to claims 65, wherein the composition includesat least one of un-hydrolyzed collagen and elastin or a mixture ofhydrolyzed or un-hydrolyzed collagen and elastin derived from eggshellmembranes.)
 78. The method according to claim 65, wherein thecomposition comprises anti-inflammatory and/or joint health promotingcompounds comprising at least one of preparations of green lipped mussel(Perna canaliculus), Boswellia serrata, turmeric (Curcuma longa),stinging nettle (Urtica dioica), Andrographis, Cat's claw (Uncariatomentosa), bromelain, methylsulfonylmethane (MSM), chondroitin sulfate,glucosamine sulfate, s-adenosyl-methionine, proanthocyanidins, orflavonoids, and preparations of hydrolyzed or un-hydrolyzed eggshellmembrane.
 79. The method according to claim 65, wherein the compositioncomprises naturally-derived and synthetic antioxidants that are added inan effective amount to retard degradation of polyunsaturated fatty acidsand astaxanthin.
 80. The method according to claim 65, wherein thephospholipids comprise 30% less of the composition.
 81. A dietarysupplement composition formulated in a therapeutic amount to treat andalleviate symptoms of joint pain in a patient wherein the compositionincludes a marine based oil comprising phospholipids and at least one ofpolyunsaturated EPA and DHA in combination with astaxanthin and lowmolecular weight hyaluronic acid or sodium hyaluronate (hyaluronan)having a molecular weight of less than 230 kDa in an oral dosage form.82. The composition according to claim 81, wherein the low molecularweight hyaluronic acid or sodium hyaluronate (hyaluronan) has amolecular weight of between 0.5 and 100 kilodaltons (kDa).
 83. Thecomposition according to claim 81, wherein the marine based oilcomprises Eicosapentaenoic (EPA) and Docosahexaenoic (DHA) fatty acidsin the form of triacylglycerides and phospholipids.
 84. The compositionaccording to claim 81, wherein the marine based oil comprises not lessthan (n.l.t.) 15 g/100 g of phospholipids, n.l.t. 12 g/100 g of DHA, andn.l.t. 7 g/100 g EPA.
 85. The composition according to claim 81, whereinthe marine based oil is enriched by the supercritical solvent extractionof the triacylglycerides bound fatty acids from phospholipids.
 86. Thecomposition according to claim 81, wherein the astaxanthin is derivedfrom Haematococcus pluvialis algae, Pfaffia, krill, or by syntheticroutes, in the free diol, monoester or diester form.
 87. The compositionaccording to claim 81, wherein the hyaluronic acid is derived from abiofermenation process.
 88. The composition according to claim 81,wherein the composition includes a natural or synthetic cyclooxygenase-1or -2 inhibitor comprising at least one of aspirin, acetaminophen,steroids, prednisone, and NSAIDs and/or a lipoxygenase inhibitor,including Boswellia serrata.
 89. The composition according to Claim 81,wherein the composition includes a gamma-linoleic acid rich oilcomprising Borage (Borago officinalis L.) or Safflower (Carthamustinotorius L.).
 90. The composition according to claim 81, wherein thecomposition includes an n-3 (omega-3) fatty acid rich fish oil, algaeoil, flax seed oil, perilla seed oil or chia seed oil and the n-3 fattyacid comprises alpha-linolenic, stearidonic, eicosapentaenoic ordocosapentaenoic acid.
 91. The composition according to claim 81,wherein the composition includes naturally-derived and syntheticantioxidants added to retard degradation of polyunsaturated fatty acidsand astaxanthin.